Sanne Hoeks

General Discussion 105 7 the induction and perpetuation of inflammatory responses during infection, and also in the pathogenesis of autoimmune and allergy-related diseases. Remarkably, we were not able to differentiate naïve T cells in cord blood into T H 17 cells in contrast to naïve T cells derived from adult blood. T H 17 differentiation in CB is blocked at the level of the lineage transcription factor, RORC2. Significantly lower RORC2 mRNA content was present in cord blood compared to T cells derived from adult blood. Neonatal T cells developed the capacity to differentiate into T H 17 cells during the first 3 months and retained a propensity to become Treg cells until the age of at least 12 months ( chapter 3 ). These data give an explanation for the observations that in neonates immunity against pathogens is established within the first 3 months while at the same time the immune system remains to have a regulatory profile. This latter fact is important in the maintenance of tolerance toward allergens and food antigens encountered for the first time. Strong danger signals can overrule the regulatory default of neonatal immunity For both Treg and T H 17 development appropriate activation by innate cells is important ( chapter 2 and 3 ). CB derived APC were much more efficient in inducing FOXP3 than adult APC. In addition, the low RORC2 content and impaired T H 17 development in CB could be explained by decreased TGFβ, IL-1β and IL-6 production by CB derived innate cells. Thus, besides intrinsic differences between neonatal and adult T cells, innate immunity (APC) plays a crucial role in balancing Treg and T H 17 cells. In chapter 5 we questioned whether the deficiency in IL-17 (and IL-6, TNFα, IFNγ and others) is absolute or can be overcome once danger signals are strong enough. We hypothesized that severe infection is a delicate model to put the neonatal immune system under ultimate stress and to provide in vivo activation of immune cells. Cerebral spinal fluid and serum samples were obtained from newborns infected with one of the neurotropic viruses ( chapter 5 ). Neonatal viral encephalopathy is often accompanied with severe white matter injury irrespective of the involved virus and with uncertain long term clinical implications. White matter injury has been considered for many years as a bystander effect of the activated immune system in viral CNS infections. Indeed, our approach showed that IL-17, as well as high levels of IL-6 and TNFα are produced in vivo during severe neonatal infections, when strong pro-inflammatory stimuli are present. These data fit previous findings in CB derived from neonates exposed to chorioamnionitis. 5-8 High cord blood frequencies of progenitor (pT H 17, CD4 + CD161 + ) and mature (mT H 17, CD4 + CD161 + CCR6 + ) T H 17 cells were found in these patients. Furthermore, IL-17 + Tregs were present in CB of preterm neonates exposed to chorioamnionitis as well as T cells with effector memory phenotype that co-expressed T H 17-type surface antigens. Simultaneously, regulatory T cells were decreased in infants exposed to chorioamnionitis relative to age- matched controls. 9 Thus, deficient innate and effector responses in neonates are partial and can be overcome once innate stimuli are strong enough. 10